Although there is much circumstantial evidence to suggest that RA and systemic lupus erythematosis (SLE) may be caused by persistent infection as the basis of an immune complex mechanism, direct cultural and immunological methods have thus far failed to confirm this. In previous work from this laboratory, a different method was devised to document the presence of micro-organisms in pathological materials. This approach is based on nucleic acid hybridization and is independent of previously used methods. Unlike these methods, the hybridization technique can, when properly controlled, give information about the absence of a given organism within its limits of sensitivity. It is based on the use of radiolabelled RNA as a specific probe to quantitive DNA from a given organism in tissue putatively infected with that organism. The method has been applied successfully to several experimental situations including chronic erysipelothrix arthritis, an animal model of RA. It is now proposed to extend these studies to the investigation of microbial persistence in the human diseases RA and SLE by a variety of approaches as well as to attempt to further increase the applicability of the hybridization technique. In addition to its use in RA and SLE, this approach is potentially useful in clarifying the causes of several other human diseases with possible therapeutic implications.